Flulaval

"Feb. 8, 2013 -- With winter cold and flu season in full swing -- and a new strain of norovirus circulating -- everyone's trying to dodge the bugs. Norovirus causes intestinal illness, and it's often the root of outbreaks at schools and in nursing"...

Flulaval

CLINICAL PHARMACOLOGY

Mechanism Of Action

Influenza illness and its complications follow infection
with influenza viruses. Global surveillance of influenza identifies yearly
antigenic variants. Since 1977, antigenic variants of influenza A (H1N1 and
H3N2) viruses and influenza B viruses have been in global circulation.

Specific levels of hemagglutination inhibition (HI)
antibody titer post-vaccination with inactivated influenza virus vaccines have
not been correlated with protection from influenza illness but the antibody
titers have been used as a measure of vaccine activity. In some human challenge
studies, antibody titers of ≥ 1:40 have been associated with protection
from influenza illness in up to 50% of subjects.1,2 Antibody
against one influenza virus type or subtype confers little or no protection
against another virus. Furthermore, antibody to one antigenic variant of influenza
virus might not protect against a new antigenic variant of the same type or
subtype. Frequent development of antigenic variants through antigenic drift is
the virological basis for seasonal epidemics and the reason for the usual
change of one or more new strains in each year's influenza vaccine. Therefore,
inactivated influenza vaccines are standardized to contain the hemagglutinins
of strains (i.e., typically 2 type A and 1 type B), representing the influenza viruses
likely to circulate in the United States in the upcoming winter.

Annual revaccination is recommended because immunity
declines during the year after vaccination, and because circulating strains of
influenza virus change from year to year.

Clinical Studies

The effectiveness of FLULAVAL was demonstrated based on
clinical endpoint efficacy data for FLULAVAL QUADRIVALENT (Influenza Vaccine),
clinical endpoint efficacy data for FLULAVAL, and on an evaluation of serum HI
antibody responses to FLULAVAL. FLULAVAL QUADRIVALENT, an inactivated influenza
vaccine that contains the hemagglutinins of two influenza A subtype viruses and
two influenza type B viruses, is manufactured according to the same process as
FLULAVAL.

Efficacy Against Influenza

Efficacy Trial in Children

The efficacy of FLULAVAL QUADRIVALENT was evaluated in
Study 5, a randomized, observer-blind, non-influenza vaccine-controlled study conducted
in 3 countries in Asia, 3 in Latin America, and 2 in the Middle East/Europe
during the 2010-2011 influenza season. Healthy subjects 3 through 8 years of
age were randomized (1:1) to receive FLULAVAL QUADRIVALENT (N = 2,584),
containing A/California/7/2009 (H1N1), A/Victoria/210/2009 (H3N2),
B/Brisbane/60/2008 (Victoria lineage), and B/Florida/4/2006 (Yamagata lineage)
influenza strains, or HAVRIX® (Hepatitis A Vaccine) (N = 2,584), as a control
vaccine. Children with no history of influenza vaccination received 2 doses of FLULAVAL
QUADRIVALENT or HAVRIX approximately 28 days apart. Children with a history of
influenza vaccination received one dose of FLULAVAL QUADRIVALENT or HAVRIX. In
the overall population, 52% were male; 60% were Asian, 5% were white, and 35% were
of other racial/ethnic groups. The mean age of subjects was 5 years.

Efficacy of FLULAVAL QUADRIVALENT was assessed for the
prevention of reverse transcriptasepolymerase chain reaction (RT-PCR)-positive
influenza A and/or B disease presenting as influenza-like illness (ILI). ILI
was defined as a temperature ≥ 100°F in the presence of at least one of
the following symptoms on the same day: cough, sore throat, runny nose, or
nasal congestion. Subjects with ILI (monitored by passive and active
surveillance for approximately 6 months) had nasal and throat swabs collected
and tested for influenza A and/or B by RT-PCR. All RT-PCR-positive specimens
were further tested in cell culture. Vaccine efficacy was calculated based on
the ATP cohort for efficacy (Table 4).

Table 4: FLULAVAL QUADRIVALENT: Influenza Attack Rates
and Vaccine Efficacy Against Influenza A and/or B in Children 3 Through 8 Years
of Agea (According toProtocol Cohort for Efficacy)

Nb

nc

Influenza Attack Rate % (n/N)

Vaccine Efficacy % (CI)

All RT-PCR-Positive Influenza

FLULAVAL QUADRIVALENT

2,379

58

2.4

55.4d (95% CI: 39.1, 67.3)

HAVRIXe

2,398

128

5.3

—

All Culture-Confirmed Influenzaf

FLULAVAL QUADRIVALENT

2,379

50

2.1

55.9 (97.5% CI: 35.4, 69.9)

HAVRIXe

2,398

112

4.7

—

Antigenically Matched Culture-Confirmed Influenza

FLULAVAL QUADRIVALENT

2,379

31

1.3

45.1g (97.5% CI: 9.3, 66.8)

HAVRIXe

2,398

56

2.3

-

CI = Confidence Interval; RT-PCR = reverse transcriptase
polymerase chain reaction.a Study 5: NCT01218308.b According to protocol cohort for efficacy included subjects who
met all eligibility criteria, were successfully contacted at least once
post-vaccination, and complied with the protocolspecified efficacy criteria.c Number of influenza cases.d Vaccine efficacy for FLULAVAL QUADRIVALENT met the pre-defined
criterion of > 30% for the lower limit of the 2-sided 95% CI.e Hepatitis A Vaccine used as a control vaccine.fOf 162 culture-confirmed influenza cases, 108
(67%) were antigenically typed (87 matched; 21 unmatched); 54 (33%) could not
be antigenically typed [but were typed by RT-PCR and nucleic acid sequence
analysis: 5 cases A (H1N1) (5 with HAVRIX), 47 cases A (H3N2) (10 with FLULAVAL
QUADRIVALENT; 37 with HAVRIX), and 2 cases B Victoria (2 with HAVRIX)].g Since only 67% of cases could be typed, the clinical significance
of this result is unknown.

In an exploratory analysis by age, vaccine efficacy
against RT-PCR-positive influenza A and/or B disease presenting as ILI was
evaluated in subjects 3 through 4 years of age and 5 through 8 years of age;
vaccine efficacy was 35.3% (95% CI: -1.3, 58.6) and 67.7% (95% CI: 49.7, 79.2),
respectively. As the study lacked statistical power to evaluate efficacy within
age subgroups, the clinical significance of these results is unknown.

The risk reduction of fever > 102.2°F/39.0°C associated
with RT-PCR-positive influenza was 71.0% (95% CI: 44.8, 84.8) based on the ATP
cohort for efficacy [FLULAVAL QUADRIVALENT (n = 12/2,379); HAVRIX (n =
41/2,398)]. The other pre-specified adverse outcomes had too few cases to
calculate a risk reduction. The incidence of these adverse outcomes is
presented in Table 5.

Table 5: FLULAVAL QUADRIVALENT: Incidence of Adverse
Outcomes Associated With RT-PCR-Positive Influenza in Children 3 Through 8
Years of Agea (Total Vaccinated Cohort)b

Adverse Outcomed

FULAVAL QUADRIVALENT
N = 2,584

HAVRIXc
N = 2,584

Number of Events

Number of Subjectse

%

Number of Events

Number of Subjectse

%

Fever > 102.2°F/39.0°C

16f

15

0.6

51f

50

1.9

Shortness of breath

0

0

0

5

5

0.2

Pneumonia

0

0

0

3

3

0.1

Wheezing

1

1

0

1

1

0

Bronchitis

1

1

0

1

1

0

Pulmonary congestion

0

0

0

1

1

0

Acute otitis media

0

0

0

1

1

0

Bronchiolitis

0

0

0

0

0

0

Croup

0

0

0

0

0

0

Encephalitis

0

0

0

0

0

0

Myocarditis

0

0

0

0

0

0

Myositis

0

0

0

0

0

0

Seizure

0

0

0

0

0

0

a Study 5: NCT01218308.b Total vaccinated cohort included all vaccinated subjects for whom
data were available.c Hepatitis A Vaccine used as a control vaccine.d In subjects who presented with more than one adverse outcome, each
outcome was counted in the respective category.e Number of subjects presenting with at least one event in each
group.fOne subject in each group had sequential influenza due to influenza
type A and type B viruses.

Efficacy Trial in Adults

The efficacy of FLULAVAL was evaluated in a randomized, double-blind,
placebo-controlled study conducted in the United States during the 2005-2006
and 2006-2007 influenza seasons (Study 3). Efficacy of FLULAVAL was defined as
the prevention of culture-confirmed influenza A and/or B cases, for vaccine
antigenically matched strains, compared with placebo. Healthy subjects 18 through
49 years of age were randomized (1:1); a total of 3,783 subjects received
FLULAVAL and 3,828 subjects received placebo [seeADVERSE REACTIONS].
Subjects were monitored for influenza-like illnesses (ILI) starting 2 weeks
postvaccination and for duration of approximately 7 months thereafter.
Culture-confirmed influenza was assessed by active and passive surveillance of
ILI. Influenza-like illness was defined as illness sufficiently severe to limit
daily activity and including cough, and at least one of the following: Fever
> 99.9°F, nasal congestion or runny nose, sore throat, muscle aches or arthralgia,
headache, feverishness or chills. After an episode of ILI, nose and throat swab
samples were collected for analysis; attack rates and vaccine efficacy were
calculated using the per protocol cohort (Table 6). Of note, the 1.2% attack
rate in the placebo group for cultureconfirmed, antigenically matched strains
was lower than expected, contributing to a wide confidence interval for the
estimate of vaccine efficacy.

CI = Confidence Interval.a Study 3: NCT00216242.b Per Protocol Cohort for efficacy included subjects with no
protocol deviations considered to compromise efficacy data.c Number of influenza cases.dLower limit of the one-sided 97.5% CI for vaccine efficacy against
influenza due to antigenically matched strains was less than the pre-defined
success criterion of ≥ 35%.

Immunological Evaluation

Adults

Study 1 was a randomized, blinded, active-controlled US
study performed in healthy adults 18 through 64 years of age (N = 1,000). A
total of 721 subjects received FLULAVAL, and 279 received a US-licensed
trivalent, inactivated influenza vaccine, FLUZONE (manufactured by Sanofi
Pasteur SA), intramuscularly; 959 subjects had complete serological data and no
major protocol deviations [see ADVERSE REACTIONS].

Analyses of immunogenicity (Table 7) were performed for
each hemagglutinin (HA) antigen contained in the vaccine: 1) assessment of the
lower bounds of 2-sided 95% confidence intervals for the proportion of subjects
with HI antibody titers of ≥ 1:40 after vaccination, and 2) assessment of
the lower bounds of 2-sided 95% confidence intervals for rates of seroconversion
(defined as a 4-fold increase in post-vaccination HI antibody titer from
prevaccination titer ≥ 1:10, or an increase in titer from < 1:10 to ≥ 1:40).
The pre-specified success criteria for HI titer ≥ 1:40 was 70% and for
seroconversion rate was 40%. The lower limit of the 2-sided 95% CI for the
percentage of subjects who achieved an HI titer of ≥ 1:40 exceeded the pre-defined
criteria for the A strains. The lower limit of the 2-sided 95% CI for the
percentage of subjects who achieved seroconversion exceeded the pre-defined
criteria for all 3 strains.

Table 7: Immune Responses to Each Antigen 21 Days
After Vaccination With FLULAVALa in Adults 18 Through 64 Years of Age (Per Protocol
Cohort)b

HI titers ≥ 1:40

FLULAVAL
N = 692
% of Subjects (95% CI)

Pre-vaccination

Post-vaccination

A/New Caledonia/20/99 (H1N1)

24.6

96.5 (94.9, 97.8)

A/Wyoming/03/03 (H3N2)

58.7

98.7 (97.6, 99.4)

B/Jiangsu/10/03

5.4

62.9 (59.1, 66.5)

Seroconversionc to:

A/New Caledonia/20/99 (H1N1)

85.6 (82.7, 88.1)

A/Wyoming/03/03 (H3N2)

79.3 (76.1, 82.3)

B/Jiangsu/10/03

58.4 (54.6, 62.1)

HI = hemagglutination inhibition; CI = Confidence
Interval.a Results obtained following vaccination with FLULAVAL manufactured
for the 2004-2005 season.b Per Protocol Cohort for immunogenicity included subjects with
complete pre- and post-dose HI titer data and no major protocol deviations.c Seroconversion defined as a 4-fold increase in post-vaccination HI
antibody titers from prevaccination titer ≥ 1:10, or an increase in titer
from < 1:10 to ≥ 1:40.

Study 2 (Immunogenicity Non-Inferiority)

In a randomized, double-blind, activecontrolled US study,
immunological non-inferiority of FLULAVAL was compared with a US-licensed
trivalent, inactivated influenza vaccine, FLUZONE, manufactured by Sanofi
Pasteur SA. A total of 1,225 adults 50 years of age and older in stable health
were randomized to receive FLULAVAL or the comparator vaccine intramuscularly [seeADVERSE REACTIONS].

Analyses of immunogenicity were performed for each HA
antigen contained in the vaccines: 1) assessment of the lower bounds of 2-sided
95% confidence intervals for the geometric mean antibody titer (GMT) ratio
(FLULAVAL/comparator), and 2) assessment of the lower bounds of 2-sided 95%
confidence intervals for seroconversion rates (defined as a 4-fold increase in
post-vaccination HI antibody titer from pre-vaccination titer ≥ 1:10, or
an increase in titer from < 1:10 to ≥ 1:40). Non-inferiority of FLULAVAL
to the comparator vaccine was established for all 6 co-primary endpoints (Table
8). Within each age stratum, immunogenicity results were similar between the
groups.

Table 8: Immune Responses to Each Antigen 21 Days
After Vaccination With FLULAVAL Versus Comparator Influenza Vaccine in Adults
50 Years of Age and Oldera (Per Protocol Cohort)b

Children

In Study 4, the immune response of FLULAVAL (N = 987) was
compared to FLUZONE, a US-licensed trivalent, inactivated influenza vaccine (N
= 979), manufactured by Sanofi Pasteur SA, in an observer-blind, randomized
study in children 3 through 17 years of age. The immune responses to each of
the antigens contained in FLULAVAL formulated for the 2009-2010 season were evaluated
in sera obtained after one or 2 doses of FLULAVAL and were compared to those
following the comparator influenza vaccine [seeADVERSE REACTIONS].

The non-inferiority endpoints were geometric mean
antibody titers (GMTs) adjusted for baseline, and the percentage of subjects
who achieved seroconversion, defined as at least a 4-fold increase in serum HI
titer over baseline to > 1:40, following vaccination, performed on the According-to-Protocol
(ATP) cohort. FLULAVAL was non-inferior to the comparator influenza for all
strains based on adjusted GMTs and seroconversion rates (Table 9).

Table 9: Immune Responses to Each Antigen 28 Days
After Last Vaccination With FLULAVAL Versus Comparator Influenza Vaccine in
Children 3 Through 17 Years of Agea (According
to Protocol Cohort for Immunogenicity)b